1. Field of the Invention
This invention relates generally to trifluoromethylepinephrine compounds and methods of making and using thereof.
2. Description of the Related Art
Anesthetic failures are common in general dental practices. See Kaufman, E. et al. (1984) J. Am. Dent. Assoc. 108-205-208. The causes of anesthetic failure relate to provider/patient factors such as technique, location of injection, anatomy, patient variability and pharmaceutical factors such as concentration and potency, pKa and pH, absorption, distribution, metabolism, excretion, degradation, and storage stability. See Hondrum, S., et al. (1993) Anesthesia and Pain Control in Dentistry 2(4):198-202.
Degradation of a pharmaceutical may occur by chemical, physical, or biological processes. The primary chemical processes that cause degradation are hydrolysis, oxidation, racemization, radiation, and incompatibility. Although degradation by hydrolysis is common with ester based local anesthetics, amide-based local anesthetics such as lidocaine and mepivacaine and the like are resistant to hydrolysis. See Cartwright, P. D. and Fyhr, P. (1988) Regional Anesth. 13:1-12. See Linter, C. J. (1980); and REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY 20th ed. Lippincott Williams and Wilkins Baltimore, Md. (2000). As amide-based anesthetics are resistant to degradation, the shelf life of dental preparations is dependent on the stability of the vasoconstrictor used.
Epinephrine and epinephrine derivatives are vasoconstrictors that are used to prolong the activity of local anesthetics in dental preparations. Epinephrine is degraded by racemization, oxidation, and bisulfite addition. See Milano, E. A., et al. (1982) J. Parenter. Sci. Technol. 36(6):232-236. It is reported that epinephrine in dental preparations may decrease to less than 85 to 90% of the initial concentration when stored under optimal conditions and less than 70% when stored under clinical conditions. See e.g. Cassidy, J. P. et al. (1986) Anesth. Prog. 33:289-297; and Gerke, D. C. et al. (1977) Aust. Dent. J. 22(6):423-427.
In some instances, it is not possible to store local anesthetics under optimal or even clinical conditions. For example, in military settings, local anesthetics are stored under harsh environmental conditions, e.g. above ambient temperatures. Therefore, there is a need for vasoconstrictors, local anesthetics, and dental preparations that exhibit enhanced resistance to hydrolysis and oxidation and a longer shelf life.
The present invention generally relates to trifluoromethylepinephrine compounds and methods of making and using the trifluoromethylepinephrine compounds.
In some embodiments, the present invention provides a compound having the following structural formula (I): 
wherein R1-R5 are each independently selected from the group consisting of H, alkyl, alkoxyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, acyl, thioacyl, sulfonyl mercapto, alkylthio, carboxy, amino, alkylamino dialkylamino, carbamoyl, arylthio, and heteroarylthio; wherein X, Y, and Z are each independently selected from the group consisting of H or trifluoromethyl with the proviso that at least one of which is trifluoromethyl.
In some preferred embodiments, R1-R5 are each independently selected from the group consisting of H and methyl. In some embodiments, X is trifluoromethyl, Y is trifluoromethyl, or Z is trifluoromethyl. In some embodiments, R1-R4 are methyl and R5 is H.
In preferred embodiments, the compound is 2-trifluoromethylepinephrine, 5-trifluoromethylepinephrine, or 6-trifluoromethylepinephrine.
In some embodiments, the compound is an (S)-enantiomer. In other embodiments, the compound is an (R)-enantiomer.
In some embodiments, the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound having the following structural formula (I): 
wherein R1-R5 are each independently selected from the group consisting of H, alkyl, alkoxyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, acyl, thioacyl, sulfonyl mercapto, alkylthio, carboxy, amino, alkylamino dialkylamino, carbamoyl, arylthio, and heteroarylthio; wherein X, Y, and Z are each independently selected from the group consisting of H or trifluoromethyl with the proviso that at least one of which is trifluoromethyl.
In some preferred embodiments, R1-R5 are each independently selected from the group consisting of H and methyl. In some embodiments, X is trifluoromethyl, Y is trifluoromethyl, or Z is trifluoromethyl. In some embodiments, R1-R4 are methyl and R5 is H.
In preferred embodiments, the compound is 2-trifluoromethylepinephrine, 5-trifluoromethylepinephrine, or 6-trifluoromethylepinephrine.
In some embodiments, the compound is an (S)-enantiomer. In other embodiments, the compound is an (R)-enantiomer.
In some embodiments, the pharmaceutical composition further comprises a supplementary active compound. In preferred embodiments, the supplementary active compound is an analgesic. In more preferred embodiments, the analgesic is a local analgesic.
The present invention also provides a compound having the following structural formula (9) 
The present invention also provides a compound having the following structural formula (10) 
The present invention also provides a compound having the following structural formula (11) 
The present invention also provides a compound having the following structural formula (12) 
The present invention also provides a method of making 2-trifluoromethylepinephrine which comprises using 3,4-dihydroxy-2-trifluoromethyl-benzaldehyde or 3-hydroxy-4-methoxybenzaldehyde as a starting product.
The present invention provides a method of detecting, measuring, or analyzing at least one epinephrine derivative in a sample which comprises conducting HPLC analysis and chiral separation on the sample.
The present invention also provides a method of inducing localized vasoconstriction in a subject which comprises administering to the subject a compound having the following structural formula (I): 
wherein R1-R5 are each independently selected from the group consisting of H, alkyl, alkoxyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, acyl, thioacyl, sulfonyl mercapto, alkylthio, carboxy, amino, alkylamino dialkylamino, carbamoyl, arylthio, and heteroarylthio; wherein X, Y, and Z are each independently selected from the group consisting of H or trifluoromethyl with the proviso that at least one of which is trifluoromethyl. In some preferred embodiments, the compound is 2-trifluoromethylepinephrine, 5-trifluoromethylepinephrine, or 6-trifluoromethylepinephrine.
In some embodiments, the present invention also provides a method of treating a disease or a disorder associated with vasodialation in a subject which comprises administering to the subject a compound having the following structural formula (I): 
wherein R1-R5 are each independently selected from the group consisting of H, alkyl, alkoxyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, acyl, thioacyl, sulfonyl mercapto, alkylthio, carboxy, amino, alkylamino dialkylamino, carbamoyl, arylthio, and heteroarylthio; wherein X, Y, and Z are each independently selected from the group consisting of H or trifluoromethyl with the proviso that at least one of which is trifluoromethyl. In some preferred embodiments, the compound is 2-trifluoromethylepinephrine, 5-trifluoromethylepinephrine, or 6-trifluoromethylepinephrine.